2 Abstract The most common reason for a patient to visit the emergency department is chest pain caused by myocar- dial ischemia. Myocardial ischemia develops from inadequate perfusion of myocardial tissue and indicates the presence of surprising range of conditions, including coronary artery disease, coronary microvascular dysfunc- tion, Takotsubo cardiomyopathy, and coronary artery dissection, and other potentially fatal cardiac diseases. Current noninvasive tests to detect ischemia may be limited by an incomplete understanding of the mecha- nisms used to induce the stress (exercise or pharmacological agents) or the limited diagnostic data acquired to visualize ischemia (12-lead electrocardiogram or ultrasound). These limitations increase the risk for failed detection of deadly cardiac diseases and explain the unsatisfactory accuracy of current diagnostic and monitor- ing approaches. The goal of this project is to leverage recent experimental ?ndings and breakthroughs about the onset and progression of ischemia as the basis for a comprehensive re-evaluation of acute myocardial is- chemia. We will develop and use experimental models and computer simulations to devise better techniques to detect acute myocardial ischemia and localize it within the ventricles. We will build on our experience with our novel large-animal experimental models of ischemia and electrocardiographic imaging (ECGI) techniques to measure and characterize the electrical changes that arise during acute myocardial ischemia created from various types of ischemic stress. We will use these measurements to characterize different types of cardiac stress and implement novel ECGI techniques to detect and localize ischemic sources within the heart.